title: Impaired innate mucosal immunity in aged mice permits prolonged Streptococcus pneumoniae colonization.
abstract: Streptococcus pneumoniae is a frequent asymptomatic colonizer of the nasopharyngeal niche and only occasionally progresses toward infection. The burden of pneumococcal disease is particularly high in the elderly, and the mechanisms behind this increased susceptibility are poorly understood. Here we used a mouse model of pneumococcal carriage to study immunosenescence in the upper respiratory tract (URT). Nasal mucosa-associated lymphoid tissue (NALT) showed increased expression of Toll-like receptor 1, interleukin-1β, NLRp3 inflammasome, and CCL2 in naive elderly compared to young animals. This suggests an increased proinflammatory expression profile in the NALT of aged mice at baseline. Simultaneously, we observed a more tolerogenic profile in respiratory epithelia of naive elderly compared to young adult mice with upregulation of the NF-κβ pathway inhibitor peroxisome proliferator-activated receptor gamma (PPARγ). After nasal instillation of pneumococci, pneumococcal colonization was prolonged in elderly mice compared to in young adults. The delay in clearance was associated with absent or delayed upregulation of a proinflammatory mediator(s) in the NALT, diminished influx of macrophages into the URT niche, and absent downregulation of PPARγ in respiratory epithelium, accompanied by diminished expression of cathelicidin (CRAMP) at the site of colonization. These findings suggest that unresponsiveness to pneumococcal challenge due to altered mucosal immune regulation is the key to increased susceptibility to disease in the elderly.
authors.affiliation: Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Krone
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Trzciński
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zborowski
authors.forename: Elisabeth A M
authors.initials: EA
authors.lastname: Sanders
authors.forename: Debby
authors.initials: D
authors.lastname: Bogaert
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D058491:Bacterial Load / Q000276:immunology; D002352:Carrier Proteins / Q000096:biosynthesis; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D053583:Interleukin-1beta / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000096:biosynthesis; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009305:Nasopharynx / Q000276:immunology / Q000382:microbiology; D047495:PPAR gamma / Q000096:biosynthesis; D011008:Pneumococcal Infections / Q000276:immunology*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000276:immunology*; D051194:Toll-Like Receptor 1 / Q000096:biosynthesis; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D002352:Carrier Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D047495:PPAR gamma; D051194:Toll-Like Receptor 1; D054804:Cathelicidins